Benzimidazole compounds, such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, and gastro esophageal reflux disorders. Benzimidazole compounds effectively inhibit gastric acid secretion.
U.S. Pat. No. 4,255,431 discloses omeprazole and therapeutically acceptable salts thereof. U.S. Pat. No. 4,738,974 specifically discloses, among other salts, the magnesium salt of omeprazole
Efforts to stabailize benzimidazole compositions using amorphous form of benzimidazole compounds are reported in literature. WO 04/037253 and WO 04/002982 teach processes of preparing amorphous forms of a salt of esomeprazole.
U.S. Pat. No. 6,713,495 discloses magnesium omeprazole having a degree of crystallinity of under 67% by weight and having a residual organic solvent content of less than 7% by weight. U.S. Patent. Application No. 2003/0232861 discloses magnesium s-omeprazole having a degree of crystallinity of under 67%. Example 3 of U.S. Pat. No. 6,713,495 and U.S. patent application No. 2003/0232861 disclose magnesium omeprazole and magnesium esomeprazole respectively, having a degree of crystallinity under 25%.
Indian application no. 1494/DEL/2003, discloses stable oral benzimidazole compositions. The compositions include a core comprising amorphous or crystalline benzimidazole compound, a substantially water-insoluble and substantially non-disintegrating separating layer and an enteric coating.
U.S. Patent Application No. 2002/0128293 teaches stable oral pharmaceutical compositions that include omeprazole and a stabilizing excipient, wherein the composition is free of alkaline compounds. Example 7 of the patent application discloses a process of wet drug layering of an inert carrier using a Wurster fluid bed apparatus.
Because of the strong tendency of benzimidazole compounds to decompose in a neutral and in particular, acidic environment, numerous approaches have been tried to form a stable pharmaceutical formulation comprising such compounds. The acid labile benzimidazole compounds react with both the gastric acid in the stomach and the enteric coatings used for preventing the benzimidazole from coming into contact with the gastric acid.
U.S. Pat. Nos. 6,274,173, 6,602,522, 5,385,739, 5,626,875, 6,159,499, 6,207,198, 5,900,124, 5,877,192, 5,690,960, 4,786,505, and 4,853,230 disclose various approaches to formulate benzimidazole compositions.
There still is a need for the development of oral pharmaceutical compositions of benzimidazole compounds which are stable, as defined herein, during formulation and storage. It has surprisingly been found that careful control of some of the processing parameters is critical to prevent the conversion of the amorphous form of benzimidazole compound to the crystalline form.
The present invention thus relates to the stable oral amorphous benzimidazole compositions and process for preparing the same as herein below described and exemplified.